Venetoclax in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) has demonstrated exceptional activity in elderly and unfit patients with newly diagnosed acute myeloid ...leukemia (AML). Notably, the safety profile of venetoclax-based induction regimens was favorable, with a low rate of early treatment-related mortality, even in frail study participants. Thus, the introduction of venetoclax has transformed the landscape of AML therapy in elderly patients. Given these promising results, venetoclax in combination with other agents is now being studied as a frontline therapy in younger patients with AML, as well as in relapsed/refractory AML patients. Here, we review clinical data for venetoclax-based therapy in AML, both from prospective as well as retrospective studies, and highlight ongoing novel studies of venetoclax-containing regimens and discuss future research directions.
Background
Blinatumomab is a CD19 BiTE (bispecific T‐cell engager) immuno‐oncology therapy that mediates the lysis of cells expressing CD19.
Methods
A pooled analysis of long‐term follow‐up data from ...2 phase 2 studies that evaluated blinatumomab in heavily pretreated adults with Philadelphia chromosome–negative, relapsed/refractory B‐cell precursor acute lymphoblastic leukemia was conducted.
Results
A total of 259 patients were included in the analysis. The median overall survival (OS) among all patients, regardless of response, was 7.5 months (95% confidence interval CI, 5.5‐8.5 months); the median follow‐up time for OS was 36.0 months (range, 0.3‐60.8 months). The median relapse‐free survival (RFS) among patients who achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) in the first 2 cycles (n = 123) was 7.7 months (95% CI, 6.2‐10.0 months); the median follow‐up time for RFS was 35.0 months (range, 9.5‐59.5 months). OS and RFS plateaued with 3‐year rates of 17.7% and 23.4%, respectively. The cumulative incidence function of the time to relapse, with death not due to relapse considered a competing risk, for patients who achieved a CR/CRh within 2 cycles of treatment also plateaued with a 3‐year relapse rate of 59.3%. For patients who achieved a CR/CRh with blinatumomab followed by allogeneic hematopoietic stem cell transplantation while in continuous CR, the median OS was 18.1 months (95% CI, 10.3‐30.0 months) with a 3‐year survival rate of 37.2%.
Conclusions
These data suggest that long‐term survival is possible after blinatumomab therapy.
Lay Summary
Immuno‐oncology therapies such as blinatumomab activate the patient's own immune system to kill cancer cells.
This study combined follow‐up data from 2 blinatumomab‐related clinical trials to evaluate long‐term survival in patients with relapsed and/or refractory B‐cell precursor acute lymphoblastic leukemia at high risk for unfavorable outcomes.
Among patients who achieved a deep response with blinatumomab, one‐third lived 3 years or longer. These findings suggest that long‐term survival is possible after treatment with blinatumomab.
Patients achieving remission after blinatumomab can have a durable response. The survival plateau indicates a high probability of a cure in those patients responding to blinatumomab and alive after 3 years.
Therapy-related acute lymphoblastic leukemia remains poorly defined due to a lack of large data sets recognizing the defining characteristics of this entity. We reviewed all consecutive cases of ...adult acute lymphoblastic leukemia treated at our institution between 2000 and 2017 and identified therapy-related cases-defined as acute lymphoblastic leukemia preceded by prior exposure to cytotoxic chemotherapy and/or radiation. Of 1022 patients with acute lymphoblastic leukemia, 93 (9.1%) were classified as therapy-related. The median latency for therapy-related acute lymphoblastic leukemia onset was 6.8 years from original diagnosis, and this was shorter for patients carrying the MLL gene rearrangement compared to those with other cytogenetics. When compared to de novo acute lymphoblastic leukemia, therapy-related patients were older (P<0.01), more often female (P<0.01), and had more MLL gene rearrangement (P<0.0001) and chromosomes 5/7 aberrations (P=0.02). Although therapy-related acute lymphoblastic leukemia was associated with inferior 2-year overall survival compared to de novo cases (46.0% vs. 68.1%, P=0.001), prior exposure to cytotoxic therapy (therapy-related) did not independently impact survival in multivariate analysis (HR=1.32; 95% CI: 0.97-1.80, P=0.08). There was no survival difference (2-year= 53.4% vs. 58.9%, P=0.68) between the two groups in patients who received allogenic hematopoietic cell transplantation. In conclusion, therapy-related acute lymphoblastic leukemia represents a significant proportion of adult acute lymphoblastic leukemia diagnoses and a subset of cases carry clinical and cytogenetic abnormalities similar to therapy-related myeloid neoplasms. Although survival of therapy-related acute lymphoblastic leukemia was inferior to de novo cases, allogeneic hematopoietic cell transplantation outcomes were comparable for the two entities.
Acute myeloid leukemia (AML) is sustained by small populations of leukemia stem cells (LSCs) that can resist available treatments and represent important barriers to cure. Although previous studies ...have shown increased signal transducer and activator of transcription (STAT)3 and STAT5 phosphorylation in AML leukemic blasts, the role of Janus kinase (JAK) signaling in primary AML compared with normal stem cells has not been directly evaluated. We show here that JAK/STAT signaling is increased in LSCs, particularly from high-risk AML. JAK2 inhibition using small molecule inhibitors or interference RNA reduced growth of AML LSCs while sparing normal stem cells both in vitro and in vivo. Increased JAK/STAT activity was associated with increased expression and altered signaling through growth factor receptors in AML LSCs, including receptor tyrosine kinase c-KIT and FMS-related tyrosine kinase 3 (FLT3). Inhibition of c-KIT and FLT3 expression significantly inhibited JAK/STAT signaling in AML LSCs, and JAK inhibitors effectively inhibited FLT3-mutated AML LSCs. Our results indicate that JAK/STAT signaling represents an important signaling mechanism supporting AML LSC growth and survival. These studies support continued evaluation of strategies for JAK/STAT inhibition for therapeutic targeting of AML LSCs.
•JAK/STAT signaling is constitutively increased in AML stem and progenitor cells.•JAK2 inhibition significantly inhibits AML but not normal stem cell growth.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic ...malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC's inaugural meetings are presented herein.
FMS‐like tyrosine kinase 3 (FLT3) mutations are prevalent in acute myeloid leukemia (AML), and their presence confers adverse risk. FLT3‐mutated (FLT3m) AML is a challenging leukemia to manage, ...particularly in older and unfit patients as well as patients with relapsed/refractory (r/r) disease. We retrospectively analyzed the outcomes of 50 FLT3m AML patients (17 treatment‐naïve, 33 r/r) treated with venetoclax (VEN) and hypomethylating agents (HMA). The overall CR/CRi rate with VEN‐HMA was 60% (94% in treatment‐naïve AML and 42% in r/r AML). Early (60‐days) treatment related mortality was 2%. The r/r AML setting was an independent predictor of lower complete response (OR: 0.08; 95%CI: 0.00‐0.60, P = .03). Cytogenetics‐molecular risk, concurrent mutations, the type of FLT3 mutation (ITD vs TKD), the ITD allelic ratio, the type of HMA, age, prior exposure to HMA and receipt of prior allogeneic transplant did not independently impact response or leukemia‐free survival (LFS). Concurrent IDH mutations were associated with lower CR/CRi (P = .01), while ASXL1 or TET2 mutations showed a non‐significant association toward higher CR/CRi (P = .07, for both). However, none of the concurrent mutations were an independent predictor for response when adjusted to AML setting. In conclusion, VEN‐HMA is associated with encouraging efficacy in FLT3m AML among both newly diagnosed unfit and r/r patients.
•Deep Learning-based model for soil-machine response during secondary tillage.•Novel method to obtain a further digitized seeding process.•Dataset with >170k in-situ collected field data points ...including depth images.•In-depth analysis of the predictive capacity of our model.•Our model can serve as basis to train intelligent control agents in simulation.
Seedbed preparation constitutes a highly important step in the crop establishment process since it directly influences both quality and yield expectation in crop fields. The quality of seedbed preparation is usually assessed by the operator of the tractor or a supervising farmer and thus dependent on qualified field personnel which are scarce today. Subsequent to the visual assessment of the current seedbed structure, a qualified operator can manually adapt the secondary tillage machine in order to optimize resource efficiency (e.g., fuel consumption) while maintaining optimal seedbed preparation according to local soil conditions. In this work, we propose to use an automated approach for real-time in-situ measurement of seedbed quality. Stereo cameras mounted in the front and the back of the tractor provide images and depth-information. Additionally, telemetry data such as working speed, power take-off (PTO) speed, fuel consumption and engine torque utilization of the tractor are logged. Based on this data, we develop a Deep-Learning-based model to predict seedbed quality (measured in form of the Roughness Coefficient), engine torque utilization and engine fuel rate. Thus, we model the interaction of the soil and the machine (soil-machine response) when preparing the seedbed with different machine configurations and environment states. For training and evaluating our model, we collected data from 16 field runs with varying soil types ranging from loamy sand to silty clay in Baden-Württemberg, Germany. Based on this data, we demonstrate that our novel model is able to predict the soil-machine response on previously unseen fields with high accuracy – in our setting with a relative root mean squared error (rRMSE) between 12.2 and 14.4 %. Our proposed model has two main advantages: (1) it allows farmers to plan the optimal machine configuration in advance by simulating different machine configurations and thus reduce the complexity for the operator and (2) it can serve as a basis for the training of intelligent control agents.
Display omitted
PDF
